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Gβγ Pathways in Cell Polarity and Migration Linked to Oncogenic

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Gβγ Pathways in Cell Polarity and Migration Linked to Oncogenic 1521-0111/90/5/573–586$25.00 http://dx.doi.org/10.1124/mol.116.105338 MOLECULAR PHARMACOLOGY Mol Pharmacol 90:573–586, November 2016 Copyright ª 2016 by The American Society for Pharmacology and Experimental Therapeutics MINIREVIEW—A LATIN AMERICAN PERSPECTIVE ON G PROTEIN-COUPLED RECEPTORS Gbg Pathways in Cell Polarity and Migration Linked to Oncogenic GPCR Signaling: Potential Relevance in Tumor Microenvironment José Vázquez-Prado, Ismael Bracho-Valdés, Rodolfo Daniel Cervantes-Villagrana, Downloaded from and Guadalupe Reyes-Cruz Departments of Pharmacology (J.V.-P., R.D.C.-V.) and Cell Biology (G.R.-C.). CINVESTAV-IPN, Mexico City, and Department of Pharmacology (I.B.-V.), School of Medicine, UABC, Mexicali, B.C., Mexico Received May 25, 2016; accepted September 14, 2016 molpharm.aspetjournals.org ABSTRACT Cancer cells and stroma cells in tumors secrete chemotactic (class I PI3Ks, b and g) and P-Rex1, a Rac-specific guanine agonists that exacerbate invasive behavior, promote tumor- nucleotide exchange factor, are fundamental Gbg effectors in the induced angiogenesis, and recruit protumoral bone marrow– pathways controlling directionally persistent motility. In addition, derived cells. In response to shallow gradients of chemotactic GPCR-dependent chemotactic responses often involve endo- stimuli recognized by G protein–coupled receptors (GPCRs), somal trafficking of signaling proteins; coincidently, endosomes Gbg-dependent signaling cascades contribute to specifying the serve as signaling platforms for Gbg. In preclinical murine models spatiotemporal assembly of cytoskeletal structures that can of cancer, inhibition of Gbg attenuates tumor growth, whereas in dynamically alter cell morphology. This sophisticated process is cancer patients, aberrant overexpression of chemotactic Gbg at ASPET Journals on September 24, 2021 intrinsically linked to the activation of Rho GTPases and their effectors and recently identified mutations in Gb correlate with cytoskeletal-remodeling effectors. Thus, Rho guanine nucleotide poor clinical outcome. Here we discuss emerging paradigms of exchange factors, the activators of these molecular switches, Gbg signaling in cancer, which are essential for chemotactic cell and their upstream signaling partners are considered participants migration and represent novel opportunities to develop pathway- of tumor progression. Specifically, phosphoinositide-3 kinases specific pharmacologic treatments. Introduction new blood vessels, and recruitment of proangiogenic cells from the bone marrow, all of which are critical to maintaining cancer In tumor microenvironments, cells adjust their shape and progression (Fig. 1) (Dorsam and Gutkind, 2007; Lappano and move in response to multiple factors secreted by cancer cells Maggiolini, 2011). and stromal cells (Friedl and Alexander, 2011; Roussos et al., Current models of GPCR-dependent chemotactic cell mi- 2011). Inherent intracellular forces are generated by actin gration have evolved from studies of fast-moving cells that polymerization and ATPase activity of myosin motors, and migrate individually, such as Dictyostelium amoebae and these mechanical responses are tightly controlled by receptor- neutrophils. These generic pathways mediating migration dependent signaling mechanisms that define the precise suggest involvement of Gbg-dependent effectors, particu- spatiotemporal reorganization of the actin cytoskeleton larly phosphatidylinositol-4,5-bisphosphate 3-kinase and (Alexander and Friedl, 2012; Devreotes and Horwitz, 2015). phosphatidylinositol (3,4,5)-trisphosphate-dependent effec- In particular, chemotactic G protein-coupled receptors tors, including guanine nucleotide exchange factors for Rho – (GPCRs) elicit G protein dependent signaling pathways GTPases. Cytoskeletal reorganization is launched by actin linked to metastatic dissemination of cancer cells, formation of nucleation sites generated by effectors of GTP-bound Rho GTPases; RhoA, Rac1, and Cdc42 are the best characterized This work was supported by Consejo Nacional de Ciencia y Tecnología members of this family of molecular switches (Fig. 2). These (CONACyT) grants [Grant 152434] and [Grant 24011] to JVP and GRC, respectively. Rho-GTPase-dependent downstream mechanisms will not dx.doi.org/10.1124/mol.116.105338. be discussed here, but readers are encouraged to consult ABBREVIATIONS: AKT, thymoma viral proto-oncogene; BMDC, bone marrow –derived cell; CaSR, calcium-sensing receptor; ERK, extracellular signal regulated kinase; GEF, guanine nucleaotide exchange factor; GPCR, G protein–coupled receptor; GRK, G protein-coupled receptor kinase; mTORC2, mammalian/mechanistic target of rapamycin complex 2; PI3K, phosphoinositide-3 kinase; PH domain, pleckstrin-homology domain; PKA, protein kinase A; RacGEF, Rac guanine nucleotide exchange factor. 573 574 Vázquez-Prado et al. Downloaded from molpharm.aspetjournals.org at ASPET Journals on September 24, 2021 Fig. 1. GPCR signaling to Rho GTPases plays a critical role in the tumor microenvironment. Cancer progression relies on the communication among different cell populations recruited into the tumor stroma. These include fibroblasts and endothelial cells from surrounding tissues and bone marrow– derived cells (BMDCs), such as macrophages, leukocytes, monocytes, endothelial progenitor cells, and other myeloid precursors. Chemokines secreted by stromal and cancer cells are key mediators of inflammation, angiogenesis, and immunosuppression, contributing to tumor growth, invasion and metastasis. Among them, several GPCR agonists in the tumor microenvironment activate signaling pathways to Rho GTPases via Ga and Gbg subunits and their RhoGEF effectors. The leading edge of migrating cells contributing to tumor progression is amplified in the inset to highlight the role of Gbg as an activator of RhoGEFs that regulate actin cytoskeleton dynamics leading chemotactic cell migration. Gbg Pathways in Oncogenic GPCR Signaling 575 Downloaded from Fig. 2. GPCR-dependent chemotaxis in individual migrating cells. A general model of chemotactic cell migration is based on studies of fast-moving individual cells, such as neutrophils and Dictyostelium molpharm.aspetjournals.org discoideum amoebas (Devreotes and Horwitz, 2015). Accordingly, a chemotactic gradient is sensed by GPCRs located at the proximity of incoming stimuli (A). Then, Gbg is locally released, recruiting PI3K and RhoGEFs (B). These effectors of Gbg promote a spatiotemporal restricted activation of Rho GTPases resulting in polarized mor- phologic changes based on the dynamics of the actin cytoskeleton (C). In this context, cell migration occurs as an integrated effect of protrusions, adhesion, and contraction at the advancing front, followed by rear-edge retraction. Maintained cell migration involves translocation of signaling proteins (D). The process is positively influenced by vesicle trafficking (Murphy et al., 2009). In this at ASPET Journals on September 24, 2021 regard, Gbg trafficking, mediated by its interaction with Rab11, activates a PI3K-AKT signaling axis at early endosomes (EE) (García-Regalado et al., 2008). Whether Gbg-trafficking leads to endosomal activation of RhoGEFs is currently being investigated. excellent reviews covering these topics (Rickert et al., 2000; migration linked to cancer progression; however, in cancer Ridley et al., 2003; Burridge and Wennerberg, 2004; Van settings, this process is further complicated by the influence Haastert and Devreotes, 2004; Charest and Firtel, 2007; of a plethora of stimuli in the microenvironment. Moreover, Ridley, 2015). General mechanisms of directional cell mi- oncogenic pathways participating in chemotactic migration gration provide a basis to explore GPCR-dependent cell are affected by mutational changes, overexpression, and 576 Vázquez-Prado et al. differential repertoire of signaling systems, which, among (Müller et al., 2001; Yagi et al., 2011), gastric carcinoma many other factors, eventually areintegratedtofacilitate (Yasumoto et al., 2006), pancreatic cancer (Marchesi et al., 2004; individual and collective migration of cancer and protumoral Xu et al., 2015), ovarian carcinoma (Barbolina et al., 2010), and cells (Fig. 1). oral cancers (Delilbasi et al., 2004; Uchida et al., 2007). We focus this review on the role of Gbg signaling in cancer. Metastatic signaling mechanisms elicited by CXCR4 involve Emphasis is given to upstream effectors leading to the activa- heterotrimeric Gi and G13 proteins. In these cases, chemotactic tion of Rho GTPases in the pathways that control chemotactic GPCRs activate Rho GTPases that control cell migration into cell migration. In this window of molecular interactions, the stroma of primary tumors and metastatic tissues. the participation of class-I PI3Ks (b and g)andP-Rex1,a Therefore, signaling pathways leading to the activation of Rac-specific guanine nucleotide exchange factor, is considered Rho GTPases are considered central players in cancer critical. We highlight the properties of P-Rex1, known to be settings (Tan et al., 2006; Yagi et al., 2011; Dillenburg-Pilla activated in concert by Gbg and phosphatidylinositol (3,4,5)- et al., 2015) (Fig. 1). As an indicator of the emerging clinical trisphosphate (Welch et al., 2002; Welch, 2015), as a putative importance of these pathways, a search for chemokine and scaffold of chemotactic signaling. The proposed role of this cancer listed 108 studies in www.ClinicalTrials.gov. multidomain effector is based on its reported interactions with Role of GPCRs,
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